Brinzolamide is a carbonic anhydrase inhibitor, R 4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazin-6-sulfonamide 1,1 dioxide, first disclosed in U.S. Pat. No. 5,378,703. It is currently formulated in an ophthalmic suspension sold under the trademark of Azopt®. Process to manufacture Brinzolamide Ophthalmic Suspension has also been disclosed in prior art, U.S. Pat. No. 6,071,904. The aforementioned patent describes a process to manufacture Brinzolamide suspension by autoclaving Brinzolamide and surfactant together followed by ball milling. This milled mixture is then added to the rest of the excipients to form a final suspension.
WO2012053011 ('011) discloses process for preparing sterile ophthalmic suspension. The process involves solubilizing Brinzolamide to get a solution which is aseptically filtered to get a filtrate which is further precipitated to get slurry of Brinzolamide. The sterile slurry of Brinzolamide is further ball milled or jet milled along with surfactants and further processed with suitable excipients.
Another approach disclosed in '011 discloses preparing aqueous solution of Brinzolamide, addition of surfactant to said aqueous solution, filtering, precipitating Brinzolamide, followed by ball milling or jet milling; further suspension vehicle is prepared and autoclaved, eventually added to slurry of Brinzolamide and surfactant.
WO2011067791 also describes another process to manufacture a Brinzolamide suspension. The process involves preparation of the slurry of Brinzolamide, followed by preparation of polymer slurry and preparation of a solution of the preservative along with the tonicity agent. The aforementioned preparations are homogenized and autoclaved followed by a sizing process. The sizing process employs a ball mill, colloidal mill or a microfluidiser. An alternately cited process involves autoclaving of Brinzolamide and the surfactant together followed by a microfluidisation process followed by addition of the rest of the excipients in a sterile manner.
Apart from specific processes claimed in prior art which relate to Brinzolamide preparation, general description with regard to preparation of suspensions containing Carbonic Anhydrase Inhibitors (CAI) are also found in prior art. These references describes preparation of sterile, topical, ophthalmic suspensions containing CAI in different ways: by way of final sterilization of a milled suspension, sterile addition of a sterile milled raw material into a sterile vehicle to form a suspension, or by aseptic addition of a sterile raw material to a sterile menstruum followed by ball milling and aseptic addition of the sterile concentrate into a sterile vehicle. These processes are not completely effective as autoclaving causes the CAI to solubilize but lead to formation of large needle like crystals on cooling down of the suspension. This is not an attractive feature especially when used in the area of Ophthalmic. Ophthalmic suspension demands that the particle size should be extremely small in order to avoid irritation on application. Smaller particle size also helps cover larger surface areas and quicker action. The desired particle size recommended is less than 10 micron.
Aseptic ball milling of the final suspension is also not feasible. This is due to unacceptable shear thinning of the polymer which occurs in the final milling step which affects the viscosity of the final suspension. Prior art also states that dry heat sterilization causes melting of the material. Sterilization by ethylene oxide introduces unacceptable degradation products and residues; gamma irradiation produces degradation products which are not acceptable.
Normally, in dry heat sterilization process, the materials are subjected to heated air at a temperature of 160° C. for 2 to 5 hours and at higher temperature of 180° C. for 1 to 3 hours or less. This conventional dry heat sterilization causes melting of the material i.e. active ingredient, specifically Brinzolamide.
The melting point of Brinzolamide is 131° C. Hence dry heat sterilization at conventional temperature causes melting and degradation of Brinzolamide. In order to avoid this problem and to achieve sterility, active ingredient is dry heat sterilized below 131° C.
Surprisingly, the inventors of the present invention have now found that effective sterilization of dry Brinzolamide can be carried out at a significant lower temperature than that considered necessary for the Dry Heat Sterilization without the problems cited in prior art.